Oral cavity and oropharyngeal squamous cell carcinomas represent the majority of oral squamous cell cancers (OSCC). Oral cavity tumors and oropharynx have different biology; however, the clinical responses of both carcinomas are very low to current treatments available. Oral cavity cancer is mostly HPV negative, and is primarily a tobacco associated malignancy. Patients with oropharyngeal tumors tend to respond better to treatment and have a better prognosis when compared to stage-matched oral cavity cancer. Novel treatment is urgently needed to improve the therapeutic efficacy of this disease to prolong the survival of the patients with oral cavity cancer. We recently identified and characterized cancer initiating cell (CIC)-enriched populations in two histologically distinct murine tumors (squamous cell cancer SCC7 and melanoma D5) using aldehyde dehydrogenase (ALDH) as a marker, and evaluated their immunogenicity by administering CIC-based dendritic cell (DC) vaccines in two genetically different syngeneic immunocompetent hosts. In addition, our team members have used ALDH as a specific marker and identified human head and neck cancer and breast cancer initiating cells respectively. Most of the current immune therapeutic methods involve individualized approaches, which significantly limits the clinical application of these methods. To help with the development of ?off-the-shelf? immunotherapies for cancer patients, cancer antigens need to be defined. We hypothesize that there exist OSCC CIC-associate/specific antigen(s) which are responsible for CIC antigenicity/immunogenicity to elicit host anti-CIC immunity. Specifically targeting cancer initiating cells will enhance the efficacy of cancer therapy. To this end, we propose to analyze the antigenicity/immunogenicity of ALDHhigh human oral cavity CICs vs. ALDHlow oral cavity non-CICs. Significantly higher antigenicity/immunogenicity of ALDHhigh human oral cavity CICs to confer anti-CIC immunity will strongly suggest the existence of unique oral cavity CIC antigens, and thus provide the rationale to isolate and characterize these antigens. Identification and characterization of immunologically and clinically relevant human oral CIC antigens as proposed to use human tumor specimens may demonstrate the proof of principle that previous findings in our animal models may be translated into human clinical trials in an autologous DC vaccine setting to present OSCC CIC specific antigen (s).